Brain cancer is a devastating disease and its most common form, glioblastoma multiforme (GBM), is responsible for 50% of all intracranial gliomas and 25% of intracranial tumors in adults. GBM diagnosis carries with it an average survival between twelve and eighteen months (with 90-95% patients surviving less than two years), without the possibility of spontaneous remission or effective treatment. The consistently short survival and absence of spontaneous remission that makes GBM such a devastating disease also render the evaluation of new therapies for this disease relatively rapid and unequivocal—overall survival represents the standard by which therapies for GBM are evaluated. Available treatment options include surgery, radiotherapy and chemotherapy.
Brain tumors are an attractive target for clinical gene therapy using viral vectors because, inter alia, the disease is rapidly fatal and no effective therapies are available [Rainov, N. G., A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme, Hum Gene Ther, 11:2389-401 (2000); Lang, F. F. et al., Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results, J Clin Oncol, 21:2508-18 (2003); Sandmair, A. M. et al., Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses, Hum Gene Ther, 11:2197-205 (2000); Klatzmann, D. et al., A phase I/II study of herpes simplex virus type 1 thymidine kinase “suicide” gene therapy for recurrent glioblastoma, Study Group on Gene Therapy for Glioblastorna, Hum Gene Ther, 9:2595-604 (1998)]. Indeed, gene therapy is an attractive novel therapeutic modality. Viral vectors can transfer genes to relatively large brain areas such as those comprising and surrounding a brain tumor [Chiocca, E. A., et al., Viral therapy for glioblastoma, Cancer J, 9:167-79 (2003); Fulci, G. et al., Oncolytic viruses for the therapy of brain tumors and other solid malignancies: a review, Front Biosci, 8:346-60 (2003); Castro, M. G. et al., Current and future strategies for the treatment of malignant brain tumors, Pharmacol Ther, 98:71-108 (2003)]. In spite of the experimental efficiency of gene therapy, human clinical trials have failed to provide major therapeutic breakthroughs [Rainov, N. G., A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme, Hum Gene Ther, 11:2389-401 (2000); Lang, F. F. et al., Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results, J Clin Oncol, 21:2508-18 (2003); Sandmair, A. M. et al., Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses, Hum Gene Ther, 11:2197-205 (2000); Klatzmann, D. et al., A phase I/II study of herpes simplex virus type 1 thymidine kinase “suicide” gene therapy for recurrent glioblastoma, Study Group on Gene Therapy for Glioblastorna, Hum Gene Ther, 9:2595-604 (1998)]. One shortcoming of previous clinical trials is that they necessarily concentrate on single therapeutic approaches (e.g., conditional cytotoxicity or immunotherapy). Further, microscopic brain tumor models used experimentally may not reflect faithfully large human tumors.
There thus remains a need in the art for effective treatments for brain cancer that obviates the aforementioned limitations, and takes advantage of gene therapeutic and direct peptide injection techniques.
The disclosures of all documents referred to throughout this application are incorporated herein by reference. The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the drawings.